Stent thrombosis is a serious medical complication associated with the implantation of stents into the vasculature system, such as in the coronary artery. The presence of both bare-metal stents (BMS) and drug-eluting stents (DES) can induce platelet adhesion, activation and thrombus formation on or near the stent. Windecker S. et al., Circulation 116:1952-65 (2007); Maisel W. H., N Engl J Med 356:981-4 (2007). Stent thrombosis can occur during the implantation of a stent into a patient, such as during percutaneous coronary intervention (PCI). Popma J. J. et al., Chest 126:576 S-99S (2004). Thrombus formation may also develop over time, with acute (<24 hours post implantation), sub-acute (>24 hours and <30 days post implantation), late (>30 days and <12 months post implantation) or very late (>12 months post implantation) stent thrombosis comprising additional complications associated with the presence of a stent within the vasculature. Given the risk of thrombus formation, anti-thrombotic therapy has been an important adjunct to PCI since its inception. Grüntzig A. R. et al., N Engl J Med 301:61-8 (1979).
Recommended anti-platelet treatments include clopidogrel, a thienopyridine platelet adenosine diphosphate (ADP) receptor blocker, which is administered during and after PCI. King S. B. 3rd. et al., Circulation 117:261-95 (2008); Silber S. et al., Eur Heart J 26:804-47 (2005). The optimal timing, loading dose, and duration of clopidogrel therapy has not been definitively established by randomized clinical trials, but current guidelines recommend a 300-600 mg clopidogrel load (preferably before the procedure) followed by 75 mg daily.
Anti-platelet treatments, such as clopidogrel treatment, are not without a risk of complications. Multiple studies have now demonstrated that the pharmacokinetic and pharmacodynamic effects of clopidogrel are highly variable (Gurbel P. A. et al., J Am Coll Cardiol 45:1392-6 (2005); Collet J. P. et al., Lancet 373:309-17 (2009)) and may be influenced by genetic polymorphisms. Mega J. L. et al., N Engl J Med 360:354-62 (2009). These biologic interactions translate into differential pharmacodynamic and therapeutic responses, leading to the notion of clopidogrel “non-responders.” Gurbel P. A. et al., Nature Clin Pract Cardiovasc Med 3:387-95 (2006). Clopidogrel also has a delayed onset of action even when given with a loading dose. Meadows T. A. et al., Circ Res 100:1261-75 (2007). Moreover, many physicians refrain from administering clopidogrel prior to angiographic definition of coronary anatomy, as this irreversible platelet inhibitor has been associated with an increased risk of perioperative bleeding if coronary artery bypass surgery is required rather than percutaneous revascularization. More potent oral ADP blockers have been tested and found to reduce ischemic outcomes even further, but with increased rates of bleeding. Wiviott S. D. et al., N Engl J Med 357:2001-15 (2007); Bhatt D. L., N Engl J Med 357:2078-81 (2007); Bhatt D. L., N Engl J Med 361:940-2 (2009); Wallentin L. et al., N Engl J Med 361:1045-57 (2009); Schomig A. et al., N Engl J Med 361:1108-11 (2009).
Thus, even in the contemporary era, the vexing problem of stent thrombosis has not been eliminated. Stone G. W. et al., N Engl J Med 360:1946-59 (2009); Bavry A. A. et al., Lancet 371:2134-33 (2008). Accordingly, there is a continuing need for potent anti-thrombotic agents with fast onset and fast offset of action that provide a desirable combination of effectiveness in treating or preventing stent thrombosis and an absence of an excessive risk of bleeding.